1. Technical Field
This invention relates generally to-permeation enhancers for electrotransport agent delivery. More particularly, this invention relates to compositions comprising different alcohols as permeation enhancers. These compositions may be incorporated into electrotransport devices for the delivery of agents, such as drugs and prodrugs, through a body surface.
2. Background Art
Drugs are most conventionally administered either orally or by injection. Unfortunately, many medicaments are completely ineffective or of radically reduced efficacy when orally administered since they either are not absorbed or are adversely affected before entering the blood stream and thus do not possess the desired activity. On the other hand, the direct injection of the medicament into the blood stream, while assuring no modification of the medicament in administration, is a difficult, inconvenient and uncomfortable procedure, sometimes resulting in poor patient compliance. Transdermal drug delivery offers improvements in these areas. The term "transdermal" is used herein in its broadest sense as the delivery of an agent through a body surface, such as the skin, mucosa, or nails. There are two major types of transdermal agent delivery, one driven by a concentration-gradient force (passive transdermal delivery), and the other driven, in addition, by a force created by applying an electrical potential (electrotransport delivery).
The tern "passive" transdermal delivery, is used herein to describe the passage of an agent through a body surface, eg, skin, in the absence of an applied electrical current. Typically, passive delivery devices have a drug reservoir which contains a high concentration of a drug. The device is placed in contact with a body surface for an extended period of time, and is allowed to diffuse from the reservoir and into the body of the patient, which has a much lower concentration of drug. The primary driving force for passive drug delivery is the concentration gradient of the drug across the skin. In this type of delivery, the drug reaches the bloodstream by diffusion through the dermal layers of the body. The preferred agents for passive delivery are hydrophobic non-ionic agents, given that the drug must diffuse through the lipid layers of the skin.
The term "electrotransport" is used herein to describe the passage of a substance, eg, a drug or prodrug, through a body surface or membrane, such as the skin, mucous membranes, or nails, induced at least partially by the application of an electric field across the body surface (eg, skin). A widely used electrotransport process, iontophoresis, involves the electrically induced transport of therapeutic agents in the form of charged ions. Ionizable therapeutic agents, eg, in the form of a salt which when dissolved forms charged agent ions, are preferred for iontophoretic delivery because the charged agent ions move by electromigration within the applied electric field. Electroosmosis, another type of electrotransport process, involves the movement of a liquid, which liquid contains a charged and/or uncharged therapeutic agent dissolved therein, through a biological membrane under the influence of an electric field. Another type of electrotransport, electroporation, involves the formation of transiently-existing pores in a living biological membrane under the influence of an electric field and delivery of a therapeutic agent therethrough. However, in any given electrotransport process, more than one of these processes may be occurring simultaneously to some extent. Accordingly, the term "electrotransport" is used herein in its broadest possible interpretation to include the electrically induced or enhanced transport of at least one agent, which may be charged, ie, in the form of ions, or uncharged, or of mixtures thereof, regardless of the specific mechanisms by which the agent is actually transported.
A common goal in both passive and electrotransport delivery is to enhance the rate of delivery of the agent. A further goal in electrotransport delivery is to reduce the electrical resistance of the skin or other body surfaces, so that the power requirements for a given level of applied electric current or drug flux will be lowered. The term "permeation enhancer" is used herein to describe additives which cause an increase in drug delivery rates both in passive and electrotransport delivery, regardless of whether the enhancement occurs by reduction of electrical or diffusional resistance.
Although there are similarities between electrotransport and passive transdermal delivery, there are also substantial differences. One difference relates to the different pathways utilized for delivery through the skin by the passive and electrotransport induced processes. Transdermal electrotransport delivery of an agent occurs within the hydrophilic pathways through the skin, ie, the sweat ducts, around hair follicles, and/or through pores, because these are the paths of least electrical resistance. On the other hand, passive transdermal delivery occurs primarily by direct diffusion through the lipid layers of the skin. Accordingly, an ideal passive permeation enhancer will disrupt the lipid layers of the skin, while an ideal electrotransport enhancer will preferably decrease the electrical resistance of the existing hydrophilic pathways in the skin. (See, Rolf, D., "Chemical and Physical Methods of Enhancing Transdermal Drug Delivery," Pharmaceutical Technology, pp 130-140 (September 1988); Cullander, C., "What are the Pathways of lontophoretic Current Flow through Mammalian Skin", Advanced Drug Delivery Reviews, 9:119-135 (1992)).
Thus, it is not surprising that many passive permeation enhancers do not enhance electrotransport delivery rates. For instance, Hirvonen et al indicate that N, N-dimethylamino acetate (DDM) and azone increase the rate of passive permeation of the agent sotalol relative to that obtained with sotalol alone (control). (Hirvonen et al, "Transdermal Permeation of Model Anions and Cations: Effect of Skin Charge, lontophoresis and Permeation Enhancers", Proceed. Intem. Symp. Control. Rel. Bioact. Mater., 19:452 (1992)). And the passage of an electric current was also shown to increase the rate of delivery of sotalol compared to that of its passive rate (control). However, the addition to solatol of either DDAA or azone reduced the rate of electrotransport of solatol compared to its rate of electrotransport without DDAA or azone (control). Clearly, DDAA and azone, both known passive permeation enhancers, were not only inoperative in electrotransport, but they actually reduced the rate of electrotransport delivery of the agent. Kontturi et al indicated that the aforementioned passive enhancers, in fact, increase skin resistivity, and advanced that passive enhancers such as those are inappropriate for use in electrotransport drug delivery. (Kontturi et al, "Electrochemical Characterization of Human Skin by Impedance Spectroscopy: The Effect of Penetration Enhancers", Pharmaceutical Research 10(3):381-385 (1993)).
Other permeation enhancers have been disclosed to be useful in passive transdermal delivery. For example, WIPO Laid Open Patent Application WO 91/16930 to Ferber et al discloses that an aqueous solution of up to 40 v/v% lower alcohol and higher alcohol in a saturating amount is suitable for enhancing passive transdermal delivery. Suitable passive transdermal delivery enhancers disclosed therein are lower C.sub.2 -C.sub.4 alcohols such as ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol, and higher alcohols such as C.sub.6 -C.sub.14 alcohols including 1-hexanol, 1-octanol, 1-nonanol, 1-decanol, 1-undecanol, 1-dodecanol, 1-tidecanol, 1-tetradecanol, 4-methyl-1-pentanol, 5-methyl-1-heptanol, 3,3-dimethyl-1-octanol, 3-cyclopentyl-1-propanol, cis-3-hexen-1-ol, trans-3-hexen-1-ol, 9-decen-1-ol and 2-octanol.
The number of permeation enhancers disclosed as useful in electrotransport delivery is considerably more limited. Ethanol, for instance, has been used as a permeation enhancer for the electrotransport delivery of polypeptides is discussed by Srinivasan et al (Srinivasan et al, "lontophoresis of Polypeptides: Effect of Ethanol Pretreatment of Human Skin," J. Pharm. Sci. 79(7):588 (July 1990)). Surfactant (eg, sodium lauryl sulfate) permeation enhancers for electrotransport drug delivery are disclosed in Sanderson et al, U.S. Pat. No. 4,722,726 and fatty acid (eg, oleic acid) permeation enhancers for electrotransport drug delivery are disclosed in Francoeur et al, U.S. Pat. No. 5,023,085.
Thus, in general, there is still a need for compositions which reduce the electrical resistance of the skin and, thus, increase agent electrotransport therethrough, producing an enhancement of the delivery rate of the agent while reducing the power requirements of the electrotransport device and/or the area of contact between the device and the body surface.